Entacapone, an inhibitor of catechol-O-methyltransferase (COMT), used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa therapy.
The chemical name of entacapone is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide. Its empirical formula is C14H15N3O5, and its, structural formula is:

Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water. It is designated chemically as (−)-L-(α-hydrazino-(α-methyl-β-(3,4-dihydroxybenzene) propanoic acid. Its empirical formula is C10H14N2O4 and its structural formula is:

Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water. It is designated chemically as (−)-L-α-amino-β-(3,4-dihydroxybenzene)propanoic acid. Its empirical formula is C9H11NO4, and its structural formula is:

U.S. Pat. Nos. 6,500,867 and 6,797,732 disclose oral solid tablet compositions comprising entacapone, levodopa and carbidopa, or pharmaceutically acceptable salts or hydrates thereof, and a pharmaceutically acceptable excipient.
U.S. Pat. No. 7,094,427 and US 20040166159 disclose a composition comprising immediate release and extended release component.
US 20080051459 discloses a method of treating Parkinson's disease comprising administering pharmaceutically effective amount of a composition comprising levodopa.
US 20070275060 disclose an extended release tablet comprising an extended release composition comprising levodopa; and an immediate or rapid release composition comprising carbidopa.
WO 07/073702 discloses a multi-layered tablet providing three different release profiles.
US 20060173074 disclose a method for the treatment of restless legs syndrome in a mammal.
Entacapone is available as immediate release composition under the trade name Comtan®. The marketed strength is 200 mg.
The triple combination of levodopa, carbidopa and entacapone is available as immediate release composition in different strengths. For example Stalevo® 50 (containing 12.5 mg of carbidopa, 50 mg of levodopa and 200 mg of entacapone), Stalevo® 75 (containing 18.75 mg of carbidopa, 75 mg of levodopa and 200 mg of entacapone), Stalevo®100 (containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone), Stalevo®125 (31.2575 mg of carbidopa, 125 mg of levodopa and 200 mg of entacapone), Stalevo®150 (containing 37.5 mg of carbidopa, 150 mg of levodopa and 200 mg of entacapone) and Stalevo®200 (containing 50 mg of carbidopa, 200 mg of levodopa and 200 mg of entacapone).
Parkinson's disease is a slowly progressive disease, in which the symptoms get worse over time. Therefore, the symptoms will change and evolve. The pattern of symptoms can vary for each person. Over a number of years, however, some people may see changes in the way their medication controls their symptoms. These changes are commonly known as motor fluctuations. Over time, symptoms begin to come back before it is time to take next dose of levodopa medication. This change in symptoms is called “wearing-off.” As “wearing-off” becomes more noticeable, the amount of time for a good response to levodopa (known as “on” time) shortens and the time for poor response to levodopa (known as “off” time) may lengthen.
In the early stages of the disease, the brain is able to store enough dopamine. This permits smoother release of dopamine in the brain. It also provides a more constant control of symptoms. However, as Parkinson's disease gets worse, the brain has fewer cells that can take up levodopa and store it as dopamine for release when levels are low. Because of this reduced ability to store dopamine in the brain, symptoms may return after shorter periods of time (e.g. “wearing-off”). If someone with a reduced ability to store dopamine is given too much levodopa, it may lead to side effects (e.g. dyskinesia).
It may be possible to better control these symptoms by changing or adjusting the treatment. As these motor fluctuations emerge, other unwanted side effects may occur. These include involuntary movements, known as dyskinesia (e.g. twisting/turning movements) or dystonia (e.g. prolonged muscle cramping). The patients treated for Parkinson's disease may frequently develop motor fluctuations characterized by end-of-dose failure, peak dose dyskinesia and akinesia, with levodopa therapy (“wearing off”) in which the patient suffers from unpredictable swings from mobility to immobility. More than 50% of patients with Parkinson's disease develop motor response fluctuations (the “wearing off” phenomenon) after treatment with levodopa therapy. Symptoms of wearing off include bradykinesia, dystonia, tremors, decreased manual dexterity, paresthesia, muscle pain, voice softness.
It is believed that the ‘wearing off’ effect can be minimized in patients with a treatment regimen, which provides less rapid dissolution properties and providing a more even plasma level profile of levodopa. When administered in conjunction with levodopa, entacapone increases the bioavailability of levodopa by facilitating its passage across the blood-brain barrier. Hence, entacapone is approved as an adjunct to levodopa therapy in Parkinson's disease. However, the dosage of currently available formulation of carbidopa, levodopa and entacapone i.e. Stalevo® is given eight times a day. The frequent dosing of these formulations is associated with more fluctuating plasma entacapone concentrations. Further, this regimen is not patient compliant.
Further, it has been observed that it is very inconvenient for the patient to take a tablet of Sinemet CR and Comtan simultaneously number of times a day, which leads to patient non-compliance especially in Parkinson's patient. Further, literature also suggests when the three ingredients are present together vis a vis entacapone, carbidopa and levodopa, it leads to decrease in bioavailability of entacapone and levodopa. Therefore, the marketed formulation Stalevo contains substantial portion of carbidopa separate from levodopa and carbidopa. Additionally, literature also reports destabilization of triple combination formulation in presence of microcrystalline cellulose.
Hence, there is a need for patient compliant entacapone composition and/or triple combination comprising levodopa, carbidopa and entacapone that will dissolve slowly and provide a more even plasma level profile in patients with entacapone or levodopa/entacapone/carbidopa treatment regimen.